2-chloro-2-phenylacetyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-phenyl-[1,2,4]triazin-5-ylamine (1.1 g, 6.4 mmol) and triethylamine (891 μl, 6.4 mmol) in anhydrous 1,2-dichloroethane (75 ml) under an atmosphere of nitrogen was added dropwise 2-chloro-2-phenylacetyl chloride (1.01 ml, 6.4 mmol). The reaction mixture was stirred at 0° C. for 90 min, then triethylamine (891 μl, 6.4 mmol) was added, and the resulting mixture heated under reflux for 30 min. The cooled reaction mixture was partitioned between CH2Cl2 (100 ml) and water (100 ml). The organic layer was separated, dried over MgSO4 and evaporated in vacuo. The solid residue was triturated with a 1:1 mixture of CH2Cl2 and MeOH (10 ml), filtered and dried to give 780 mg (2.7 mmol, 42%) of 3,8-diphenylimidazo[1,2-d][1,2,4]triazin-2-ol as a pale yellow solid. δH (360 MHz; DMSO-d6) 7.41 (1H, t, J 7.3 and 7.2, aromatic), 7.50-7.63 (5H, m, aromatics), 7.82 (2H, d, J 7.8, aromatics), 8.57 (2H, m, aromatics), 9.65 (1H, s, imidazotriazine H5), 11.72 (1H, br s, OH); m/z (ES+) 289 (M++H, 100%). the resulting mixture heated under reflux for 30 min The cooled reaction mixture was partitioned between CH2Cl2 (100 ml) and water (100 ml) The organic layer was separated dried over MgSO4 evaporated in vacuo The solid residue was triturated with a 1:1 mixture of CH2Cl2 and MeOH (10 ml) filtered dried

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 150 ml. of concentrated ammonium hydroxide and 75 g. of ice was added 20 g. of 2-chloro-2-phenylacetylchloride. The amide formed immediately. The reaction mixture was stirred for 30 minutes and the white solid precipitate which was collected weighed 16.9 g. This precipitate was dissolved in 100 ml. of hot ethyl acetate and then diluted with petroleum ether, after which there was collected 14.3 g. of white cottony needles having an m.p. of 120°-121° C. of ice was added 20 g

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 150 ml. of concentrated ammonium hydroxide and 75 g. of ice was added 20 g. of 2-chloro-2-phenylacetylchloride. The amide formed immediately. The reaction mixture was stirred for 30 minutes and the white solid precipitate which was collected weighed 16.9 g. This precipitate was dissolved in 100 ml. of hot ethyl acetate and then diluted with petroleum ether, after which there was collected 14.3 g. of white cottony needles having an m.p. of 120°-121° C. of ice was added 20 g

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (2 g) was added portionwise to a solution of 3,5-dimethylphenol (6.1 g) in DMF (50 ml). The mixture was stirred for 30 minutes and added dropwise at a temperature below 30° C. to a solution of 2-chloro-2-phenylacetylchloride (9.45 g) in DMF (50 ml). The mixture was stirred overnight, decomposed with water (5 ml) and the solvent was evaporated. Water was added and the mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: hexane/DIPE 100/0, 98/2 and 95/5). The pure fractions were collected and the solvent was evaporated [residue; yielding 10.82 g (79%)]. A small amount of the obtained residue was crystallized from DIPE, the precipitate was filtered off and the solvent was evaporated, yielding 1 g of (±)-3,5-dimethylphenyl α-chlorobenzeneacetate (intermediate 5; mp. 79.0° C.). The mixture was stirred overnight the solvent was evaporated Water was added the mixture was extracted with DCM The separated organic layer was dried filtered the solvent was evaporated The residue was purified over silica gel on a glass filter (eluent: hexane/DIPE 100/0, 98/2 and 95/5) The pure fractions were collected the solvent was evaporated [residue; yielding 10.82 g (79%)] A small amount of the obtained residue was crystallized from DIPE the precipitate was filtered off the solvent was evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, triethylamine (0.153 mL) and tetrahydrofuran (5.0 mL) was added chloro(phenyl)acetylchloride (0.174 mL) with stirring at room temperature. The reaction mixture was stirred for 10 min, and pyrrolidine (0.42 mL) was added. The reaction mixture was stirred with heating at 70° C. for 1 hr, and the reaction system was concentrated under reduced pressure. To the residue was added 2M aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred with heating at 120° C. for 2 hr. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane). The obtained yellow solid was washed with ethyl acetate (2 mL) to give the title compound (330 mg) as a yellow solid. The reaction mixture was stirred for 10 min The reaction mixture was stirred with heating at 70° C. for 1 hr the reaction system was concentrated under reduced pressure To the residue was added 2M aqueous sodium hydroxide solution (1.5 mL) the mixture was stirred with heating at 120° C. for 2 hr The mixture was extracted with ethyl acetate dried over anhydrous sodium sulfate Insoluble material was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) The obtained yellow solid was washed with ethyl acetate (2 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, triethylamine (0.153 mL) and tetrahydrofuran (5.0 mL) was added chloro(phenyl)acetylchloride (0.174 mL) with stirring at room temperature. The reaction mixture was stirred for 10 min, and pyrrolidine (0.42 mL) was added. The reaction mixture was stirred with heating at 70° C. for 1 hr, and the reaction system was concentrated under reduced pressure. To the residue was added 2M aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred with heating at 120° C. for 2 hr. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane). The obtained yellow solid was washed with ethyl acetate (2 mL) to give the title compound (330 mg) as a yellow solid. The reaction mixture was stirred for 10 min The reaction mixture was stirred with heating at 70° C. for 1 hr the reaction system was concentrated under reduced pressure To the residue was added 2M aqueous sodium hydroxide solution (1.5 mL) the mixture was stirred with heating at 120° C. for 2 hr The mixture was extracted with ethyl acetate dried over anhydrous sodium sulfate Insoluble material was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) The obtained yellow solid was washed with ethyl acetate (2 mL)